Reducing Chemo-/Radioresistance to Boost the Therapeutic Efficacy against Temozolomide-Resistant Glioblastoma

Abstract

Chemo-/radioresistance is the most important reason for the failure of glioblastoma (GBM) treatment. Reversing the chemo-/radioresistance of GBM for boosting therapeutic efficacy is very challenging. Herein, we report a significant decrease in the chemo-/radioresistance of GBM by the <i>in situ</i> generation of SO₂ within a tumor, which was released on demand from the prodrug 5-amino-1,3-dihydrobenzo[<i>c</i>]thiophene 2,2-dioxide (ATD) loaded on rare-earth-based scintillator nanoparticles (<i>i.e.</i>, NaYF₄:Ce@NaLuF₄:Nd@ATD@DSPE-PEG₅₀₀₀, ScNPs) under X-ray irradiation. Our novel X-ray-responsive ScNPs efficiently converted highly penetrating X-rays into ultraviolet rays for controlling the decomposition of ATD to generate SO₂, which effectively damaged the mitochondria of temozolomide-resistant U87 cells to lower the production of ATP and inhibit P-glycoprotein (P-gp) expression to reduce drug efflux. Meanwhile, the O⁶-methylguanine-DNA methyltransferase (MGMT) of drug-resistant tumor cells was also reduced to prevent the repair of damaged DNA and enhance cell apoptosis and the efficacy of chemo-/radiotherapy. The tumor growth was obviously suppressed, and the mice survived significantly longer than untreated temozolomide-resistant GBM-bearing mice. Our work demonstrates the potential of SO₂ in reducing chemo-/radioresistance to improve the therapeutic effect against resistant tumors if it can be well controlled and <i>in situ</i> generated in tumor cells. It also provides insights into the rational design of stimuli-responsive drug delivery systems for the controlled release of drugs.